Katsube Takayuki, Miyazaki Shiro, Narukawa Yukitoshi, Hernandez-Illas Martha, Wajima Toshihiro
Clinical Pharmacology & Pharmacokinetics, Shionogi & Co., Ltd., Osaka, Japan.
Drug Metabolism & Pharmacokinetics Department, Shionogi & Co., Ltd., Toyonaka, Osaka, Japan.
Eur J Clin Pharmacol. 2018 Jul;74(7):931-938. doi: 10.1007/s00228-018-2458-9. Epub 2018 Apr 7.
Cefiderocol, a siderophore cephalosporin, will be used concomitantly with other medications for treatment of bacterial infections. In vitro studies demonstrated inhibition potential of cefiderocol on organic anion transporter (OAT) 1, OAT3, organic cation transporter (OCT) 1, OCT2, multidrug and toxin extrusion (MATE) 2-K, and organic anion transporting polypeptide (OATP) 1B3. The aim of this study was to assess in vivo drug-drug interaction (DDI) potential of cefiderocol using probe substrates for these transporters.
DDI potentials of cefiderocol as inhibitors were assessed in a clinical study consisting of 3 cohorts. Twelve or 13 healthy adult subjects per cohort orally received a single dose of furosemide 20 mg (for OAT1/3), metformin 1000 mg (for OCT1/2 and MATE2-K), or rosuvastatin 10 mg (for OATP1B3) with or without co-administration with cefiderocol 2 g every 8 h with 3-h infusion (a total of 3, 6, and 9 doses of cefiderocol with furosemide, metformin, and rosuvastatin, respectively). DDI potentials were assessed based on the pharmacokinetics of the substrates.
Ratios (90% confidence intervals) of maximum plasma concentration and area under the plasma concentration-time curve were 1.00 (0.71-1.42) and 0.92 (0.73-1.16) for furosemide, 1.09 (0.92-1.28) and 1.03 (0.93-1.15) for metformin, and 1.28 (1.12-1.46) and 1.21 (1.08-1.35) for rosuvastatin, respectively. Exposures to furosemide or metformin did not change when co-administered with cefiderocol. Slight increase in rosuvastatin exposure was observed with co-administered with cefiderocol, which was not considered to be clinically significant. Each treatment was well tolerated.
Cefiderocol has no clinically significant DDI potential via drug transporters.
头孢地尔，一种铁载体头孢菌素，将与其他药物联合用于治疗细菌感染。体外研究表明头孢地尔对有机阴离子转运体（OAT）1、OAT3、有机阳离子转运体（OCT）1、OCT2、多药和毒素外排转运体（MATE）2-K以及有机阴离子转运多肽（OATP）1B3具有抑制潜力。本研究的目的是使用这些转运体的探针底物评估头孢地尔在体内的药物相互作用（DDI）潜力。
在一项包含3个队列的临床研究中评估了头孢地尔作为抑制剂的DDI潜力。每个队列的12名或13名健康成年受试者口服单剂量20毫克呋塞米（用于评估OAT1/3）、1000毫克二甲双胍（用于评估OCT1/2和MATE2-K）或10毫克瑞舒伐他汀（用于评估OATP1B3），同时或不同时每8小时静脉输注2克头孢地尔（输注3小时）（分别与呋塞米、二甲双胍和瑞舒伐他汀共用3、6和9剂头孢地尔）。根据底物的药代动力学评估DDI潜力。
呋塞米的最大血浆浓度和血浆浓度-时间曲线下面积的比值（90%置信区间）分别为1.00（0.71-1.42）和0.92（0.73-1.16），二甲双胍分别为1.09（0.92-1.28）和1.03（0.93-1.15），瑞舒伐他汀分别为1.28（1.12-1.46）和1.21（1.08-1.35）。与头孢地尔合用时，呋塞米或二甲双胍的暴露量没有变化。与头孢地尔合用时，观察到瑞舒伐他汀的暴露量略有增加，但这在临床上不被认为具有显著意义。每种治疗的耐受性都良好。
头孢地尔通过药物转运体没有临床显著的DDI潜力。
